Project Summary This application is a competitive renewal of R01-CA-113941 and seeks to address the needs of heath care, particularly in the area of cancer. The overall goal of our project is to investigate and improve time-of-flight (TOF) PET imaging, and to develop technology for the next generation of TOF PET imaging instruments. Advanced technology for TOF PET is already under development, and we designed this application to carry on this work. Even with technology available commercially today, TOF has been shown to improve the quality of the reconstructed images and aid in the clinical interpretation of disease. The TOF technique requires an accurate measurement of the time difference between the two 511-keV gamma rays that result from the positron annihilation of the radioactive isotope (e.g., 18F) tagged to the PET tracer. TOF PET systems depend on fast scintillation detectors and triggering electronics to measure and record the TOF information accurately, as well as data correction and image reconstruction algorithms that incorporate the TOF information. We have developed PET detectors, both lanthanum bromide (LaBr3) and lutetium (yttrium) oxyorthosilicate (LYSO), which have excellent timing performance for TOF as well as sensitivity, energy resolution and spatial resolution required for state-of-the-art whole-body PET imaging. We have completed construction and initial testing of a research proto-type scanner based on lanthanum bromide detectors (La-PET) and we have achieved a system timing resolution of 375 ps, energy resolution of 7%, and spatial resolution of 5.8 mm. In addition we have performed extensive measurements with the Philips Gemini TF PET/CT scanner in our clinic to evaluate TOF PET with patient data as well as phantoms. This scanner utilizes LYSO with an intrinsic timing resolution of 600 ps, but operates at about 650 ps for typical patient studies. Availability of both TOF PET scanners provides us with a unique opportunity to assess the relative impact of timing resolution compared to the conventional metrics of performance, including spatial resolution and sensitivity. We plan to take a systems approach to evaluate each component of the system, first to optimize the existing technology, and to guide the development of new techniques for improved performance. Each major factor affecting system performance - the scintillation detector, the calibrations and processing electronics, data correction techniques, and the image reconstruction algorithm - will be studied independently and as part of the system. Evaluation of these factors will be defined in terms of their impact on image quality and quantification and their effects on the tasks involved in the study of cancer and other disease using PET, such as lesion detectability and lesion contrast estimation. We will use methodologies that are predictive of the human's ability to identify and quantify activity uptake in lesions, thus guiding the utilization of TOF PET for the study of cancer.